Hydrogel Wound Coverings

ABSTRACT

A method of preparing a hydrogel wound covering from polymers by irradiation cross-linking is disclosed. An initial aqueous solution comprising at least 15% of a synthetic polymer cross-linkable by irradiation, at least one humectant, a natural polymer and water, is poured into a mould for shaping. Then the initial aqueous solution is allowed to mature in the mould during a period of time sufficient to obtain a semi-product having at least a content of 35% of synthetic polymer. Thereafter the semi-product thus shaped is removed from the mould and subjected to irradiation in order to cross-link and sterilize the semi-product. A hydrogel wound covering is also disclosed.

The present invention relates to a method of preparing hydrogel woundcoverings from polymers by irradiation cross-linking for use on animalbodies, in particular human bodies. The present invention also relatesto a hydrogel wound covering thus prepared.

Such a method of manufacturing hydrogel wound coverings from syntheticand natural polymers by irradiation polymerisation is known in the art,for example from U.S. Pat. No. 4,871,490 in the name of Rosiak et al.This known method comprises the steps of pouring an aqueous solution ofa synthetic polymer, for example polyvinylpyrrolidone (PVP), a naturalpolymer like agar, a so-called plasticizing agent such as polyethyleneglycol (PEG) into a mould imparting a shape to the covering. The mouldis closed, and then the composition contained in the mould is subjectedto an irradiation dose of at least 25 kGy. According to this patent theaqueous solution has a composition of 2-20% by weight of syntheticpolymers, not more than 5% by weight of natural polymers, not less than75% by weight of distilled water and 1-3% by weight of plasticizingagent. A polyvinylpyrrolidone hydrogel according to this patent iscurrently marketed in Poland and some parts of central Europe under thetrade name AQUA-GEL. The commercial formulation consists of 7% PVP, 1.5%polyethylene glycol and 1% agar. This formulation is said to be a goodburn dressing, though its mechanical, swelling and drying propertiesleave something to be desired.

U.S. Pat. No. 5,540,033 in the name of Fox et al. discloses a method ofproducing a sterile packaged adhesive hydrogel product by preparing anaqueous mixture of water, a polymer cross-linkable by radiation to forma hydrogel, and a cross-linking inhibitor in an amount sufficient toretard the cross-linking of the polymer when the mixture is exposed toradiation. Next the mixture thus prepared is shaped into aconfiguration, which is representative of the desired hydrogel product.Following shaping, the shaped mixture is enclosed in a sealed package,and subjected to a dose of radiation sufficient to simultaneouslycross-link and sterilize the mixture in order to obtain the finalhydrogel product. Preferred polymers used in this known method includepolyethylene oxide, polyvinylpyrrolidone or mixtures thereof. Apreferred cross-linking inhibitor is a food grade antioxidant likeascorbic acid. The polyvinylpyrrolidone is typically a polymer ofN-vinyl-2-pyrrolidone having a weight average molecular weight of about200,000-2,000,000 Dalton, advantageously around 1,000,000. The preferredconcentration of polyvinylpyrrolidone in the aqueous mixture is about 10to 35 weight %, most preferably 15 to 25 weight %. Additional additivescan be included in the formulation. It is said that a humectant such aspolyethylene glycol can be used to improve the physical properties ofthe hydrogel, in particular to extend the life-time thereof. In additionto the cross-linking inhibitor, a cross-linking promoter can be present.Ethylene glycol dimethacrylate is one of the examples mentioned of suchcross-linking promoters. This known method can provide hydrogels having% gel values of at least about 80%. The absorptive capacity of thehydrogels, measured by the gel ratio, can be at least about 5.

U.S. Pat. No. 5,578,661 in the name of Fox et al. discloses agel-forming system for use in wound dressings. This know gel-formingsystem comprises an aqueous mixture of at least three polymericcomponents. The first polymeric component comprises a water-solublepolymer in an amount sufficient to increase the initial viscosity of themixture and impart adhesive properties thereto. An example of such awater-soluble polymer is polyvinylpyrrolidone, which is advantageouslypresent in an amount of between about 3 and 35% by weight of the gel-forming system. A hydrophilic water-soluble polymer mixture ofpolyvinylpyrrolidone and polyethylene oxide in a weight ratio of about10/1 and 25/1 is preferred, wherein the polyvinylpyrrolidone is presentin an amount in the range of about 10 to 25% by weight of the system.The second polymeric component is an acid-containing polymer, preferablya polymer of an acid or acid-forming compound or a copolymer of an acidof acid-forming compound and a monomer which forms a water-solublecompound. The third polymeric component is an amino-containing polymer,which is advantageously present in an amount in the range of 0.5 to 5%by weight. Among the preferred third components are heparin and agar.Additional additives like bactericides and antibiotics, can be presentat a concentration of about 0.001 to about 3% by weight of the system. Ahumectant can be included in the gel-forming system in order to increasethe solubility of the third or second component in the mixture.Polyethylene glycol is mentioned as one of the preferred humectants.Such a humectant may be present at a concentration of about 1 to 40%,preferably 5 to 20% by weight of the system. The examples presented inthis patent are directed to formulations having a polyvinylpyrrolidonecontent of 10% of the mixture, wherein also polyethylene oxide ispresent. The gel ratio as a measure of the adsorption capacity of thehydrogels can exceed 5.

U.S. Pat. No. 5,480,717 in the name of Kundel discloses processes foradhering a polymeric hydrogel to a substrate in order to obtain ahydrogel laminate with greatly improved delamination resistance.According to this patent a preferred hydrogel is cross-linkedpolyvinylpyrrolidone. The preferred polyvinylpyrrolidone polymers have aviscosity average molecular weight of about 150.000-450.000, andpreferably about 200.000-300.000 Dalton. The hydrogel preferablycomprises about 30 to 60, preferably about 40 to 50 weight % of thepolymer complemented by about 40 to 70, preferably 50 to 60 weight % ofwater. It is said that if the molecular weight of thepolyvinylpyrrolidone is too high it is not possible to make a solutionwith a high enough polyvinylpyrrolidone concentration, and as a resultthe adhesion to the polymeric adhesive layers after irradiation is notacceptable.

U.S. Pat. No. 5,306,504 discloses adhesive hydrogel compositions basedon a cross-linked polyvinylpyrrolidone. The adhesive hydrogelcomposition is prepared by mixing in an aqueous medium a water-solublehigh molecular weight polyvinylpyrrolidone having ring openedpyrrolidone groups providing at least 1.5×10⁻² milliequivalents ofcarboxylic acid groups per gram of polymer, and a water-solublemultifunctional amine-containing polymer. The acid groups of the ringopened polyvinylpyrrolidone and the basic amine groups of themultifunctional amino-containing polymer are allowed to react in orderto form a water-insoluble, water-swellable cross-linked ampholyte salt.The preparation takes place in an aqueous medium with a water content ofabout 40 to about 80% by weight. A plasticizer for tack development maybe included in the reacting medium. An example of such a plasticizer ispolyethylene glycol. The plasticizer may be resent in the range of20-55% by weight, based on the combined eight of the cross-linkedpolyvinylpyrrolidone and the plasticizer. Although the plasticizer mayincrease tack, it decreases gel strength.

U.S. Pat. No. 4,646,730 in the name of Schonfeld et al. discloses thecolor stabilization of a polyvinylpyrrolidone based hydrogel dressing bythe addition of magnesium trisilicate and optionally hydrogen peroxideand/or polyacrylate acid.

WO 03/034900 (EPICEPT CORPORATION) discloses an intradermal patch havinga permeable backing, which is coated with a polyvinylpyrrolidone basedhydrogel, containing one or more local anaesthetics. Preferably thehydrogel is a polyvinylpyrrolidone having an average molecular weight ofabout 500.000 to about 2.000.000 Dalton, more preferably about 900.000Dalton to about 1.500.000 Dalton. The pre-gel hydrogel mixture, fromwhich the patches according to this patent application are prepared,comprises a homogeneous mixture of about 5% to about 35% by weight,preferably about 10% to about 30%, more preferably about 15% to about20% by weight of polyvinylpyrrolidone, and about 0.5% to about 20%,preferably about 2% to about 10% of a local anesthetic. The patches maycomprise one or more additional components, like preservatives,stabilizers, absorptive agents, wound-healing agents, electrolyte andtonicity agents, viscosity-enhancing agents like agar, medicines,bioadhesive polymers, penetration enhancers and humectants.

The object of the present invention is to improve the physicalproperties of the hydrogel material in a wound covering. In particularthe invention aims at improving the mechanical, swelling and dryingproperties thereof.

The method according to the invention of preparing hydrogel woundcoverings from polymers by irradiation cross-linking comprises the stepsof providing an initial aqueous solution comprising at least 15% of asynthetic polymer cross-linkable by irradiation, based on the weight ofthe mixture, at least one humectant, a natural polymer and water,pouring the initial aqueous solution into a mould for shaping, allowingthe aqueous solution to mature in the mould during a period of timesufficient to obtain a semi-product having a content of at least 35% ofsynthetic polymer, removing the semi-product thus shaped from the mould,and subjecting the semi-product to irradiation in order to cross-linkand sterilise the semi-product. In the method according the inventionthe aqueous solution comprises at least 15% of a synthetic polymer,which is cross-linkable by irradiation, based on the weight of themixture. This amount of synthetic polymer is required to impart therequired mechanical strength of the semi-product allowing furtherprocessing into the hydrogel product finally obtained. The preferredsynthetic polymers cross-linkable by irradiation comprisepolyvinylpyrrolidone, preferably having a weight average molecularweight of at least 300,000 Dalton.

Polyvinylpyrrolidone with such a high molecular weight does not dissolvein water homogeneously at concentrations over 30%. Therefore accordingto the invention it is necessary to prepare a more diluted startingsolution and to allow the aqueous solution to mature in the mould duringa period of time sufficient to obtain a homogeneous semi-product havinga content of at least 35% of synthetic polymer. In addition to thesynthetic polymer the aqueous solution comprises a humectant, preferablypolyethylene glycol in order to improve the swelling properties of thehydrogel. The natural polymer used in the present invention ispreferably agar, which is advantageously present in the range of0.5-3.0% by weight in the solution. The aqueous solution can easily beprepared by mixing the original components in the required amounts intowater. Thereafter the aqueous solution is poured into a mould in orderto shape it into the desired configuration.

According to the invention the aqueous solution is allowed to mature inthe mould during a period of time, that is sufficient to obtain asemi-product having at least a content of 35% of synthetic polymer.During this maturation period, water is partially liberated from thesemi-product and evaporated, but most importantly the chains of thesynthetic polymer, natural polymer and humectant undergo relaxation. Byrelaxation these components take thermodynamically preferred positionswith the result that the concentrated components are homogenouslydistributed in water. After removal of the semi-product from the mould,the semi-product is subjected to irradiation in order to cross-link andsterilize the semi-product, e.g. by electron beams or γ-rays.

The duration of the maturation period is dependent from the initialconcentration of the polymers and other components, the thickness of thelayer in the mould, and the temperature at which the maturation occurs.Typically maturation can be carried out by allowing the composition tostand overnight at ambient temperature. Preferably the maturation periodof time is at least 15 hours, at room temperature or slightly above.

In principle, other water-soluble synthetic polymers may be present inthe initial aqueous solution in addition to polyvinylpyrrolidone, buttheir amount should be limited to a relatively small concentration suchas 1-2%. The actual limit is dependent from the molecular weight of therespective polymer. The higher the molecular weight, the smaller theamount that will dissolve. Examples of such other water-solublesynthetic polymers comprise polyethyleneoxide (PEO), polyacrylamide(PAA), polyvinylalcohol (PVA) and polyacrylic acid. Polyethylene glycolis considered a humectant instead of a water-soluble synthetic polymerin the context of this specification.

The method according to the invention advantageously comprises anadditional step of applying an adhesive plastic foil for adhesion to theskin onto the semi-product that has been removed from the mould. Apreferred plastic foil is permeable to water vapour. Suitable adhesivesand plastic foils are known in the art, e.g. from the patent literaturecited above, and e.g. foils from 3M Company for medical purposes.

Advantageously the method also comprises the step of sealing thesemi-product and adhesive plastic foil into a suitable packagingmaterial prior to the irradiation treatment.

More preferably the final shape of the hydrogel coverings is obtainedafter maturation of the aqueous solution in the mould. In other wordsthe semi-product is divided into articles having appropriate dimensions,e.g. cut into pieces, covered with adhesive plastic foil and then packedand sterilized.

Preferably the aqueous solution also comprises a cross-linking agent,because the presence of the humectant may decrease the gel fraction ofthe hydrogel wound covering. Preferably the amount of cross-linkingagent is kept as low as possible, because the presence of thecross-linking may affect the transparency of the hydrogel. Additionaladditives may be present in the hydrogel wound covering according to theinvention. Examples of suitable additives comprise preservatives,medicaments and antibacterial agents like allantonin. Allantonin is amedically acceptable antibacterial agent. It inhibits the growth ofpathogenic microorganisms prior to irradiation of the semi-product.

The invention also relates to a hydrogel wound covering comprising aradiation cross-linked synthetic polymer in an amount of at least 35% byweight, a humectant and a natural polymer.

Preferably the covering comprises at least 2% by weight humectant, mostpreferably polyethylene glycol, and 0.5-3% by weight natural polymersuch as agar.

The invention also relates to a packaged hydrogel wound dressing articlecomprising a hydrogel of a radiation cross-linked synthetic polymer inan amount of at least 35% by weight, a humectant and a natural polymerand an adhesive plastic foil, wrapped in a suitable packaging material.

A preferred aqueous solution used as starting material in the methodaccording to the invention comprises:

-   20% polyvinylpyrrolidone (tradename: Kollidon K-90 (BASF))-   10% polyethylene glycol (tradename: Lutrol 400 (BASF)-   1% agar (available from Bristol Laboratories)-   0-0.5% cross-linking agent, and-   about 0.1% antibacterial agent-   remainder (up to 100% distilled water).

After preparation of the semi-product and maturation during the nightthe preferred composition of the semi-product is about 35%polyvinylpyrrolidone, about 17% polyethylene glycol and 1.7% agar, whilethe concentration of the remaining components increases about 2 timeswith respect to the starting material.

After packaging the semi-product is sterilized with a dose of about 25kGy.

Herein below the invention is illustrated in more detail, includingreference to the attached drawing, wherein:

FIG. 1 shows the effect of a humectant on the swelling properties of ahydrogel;

FIG. 2 shows the effect of a humectant on the drying properties of ahydrogel;

FIG. 3 shows the effect of a cross-linking agent on the wellingproperties of a hydrogel;

FIG. 4 shows the effect of a cross-linking agent on the percentagedrying of PVP hydrogel;

FIG. 5 shows the percentage drying of a PVP hydrogel according to theinvention versus a commercially available PVP hydrogel;

FIG. 6 shows the percentage swelling of a PVP hydrogel according to theinvention versus a commercially available PVP hydrogel.

In the fig. “initial weight” means initial weight of ready hydrogel(after maturation and irradiation), and “initial solution” refers to theconcentration of components in solution before maturation andirradiation.

The following properties of samples of the following examples weremeasured:${{Percentage}\quad{Swelling}\quad(\%)} = {\frac{{{{wt}.\quad{swollen}}\quad{hydrogel}} - {{initial}\quad{{wt}.\quad{hydrogel}}}}{{initial}\quad{{wt}.\quad{hydrogel}}} \times 100}$${{Percentage}\quad{Drying}\quad(\%)} = {\frac{{wt}.\quad{hydrogel}}{{initial}\quad{{wt}.\quad{hydrogel}}} \times 100}$${{Gel}\quad{fraction}} = \frac{{{wt}.\quad{dry}}\quad{gel}}{{{wt}.\quad{of}}\quad{PVP}\quad{in}\quad{semi}\text{-}{product}}$

Different concentrations of PVP hydrogel (15%, 18%, 20% concentration ofPVP in stock solution) were prepared using different amounts of PEG andagar. Irradiation of the polymeric mixtures was performed using a linearaccelerator at an adsorbed dose of 25 kGy. The dose said was calibratedwith a water calorimeter. Manual examination of the hydrogels thusprepared revealed that the 20% PVP mixture had the best mechanicalproperties.

The swelling and drying properties of this hydrogel were tested using abalance with different amounts of PEG (0-10%) in the solution (beforematuration). In general, addition of PEG can retard the drying process.FIG. 1 shows the effect of varying PEG concentration in the PVP hydrogel(20% PVP, 1% agar) on the swelling properties at 37° C. It is apparentthat the percentage swelling increases with increasing PEGconcentration. At 10% PEG, equilibrium swelling reaches a maximum ofabout 400%. Such a high equilibrium swelling is an indication of theadsorption capacity of the hydrogel wound covering. As shown in Table 1below, gel fraction decreases to 0.58 at 10% PEG. TABLE 1 Gel fractionof PVP hydrogel (20% PVP, 1% agar) with different concentrations of PEG% PEG Gel fraction 0 0.90 0.75 0.90 1.5 0.90 3 0.88 5 0.94 10 0.58Gel fraction can be related to cross-linking density, which in its turncan directly effect the mechanical properties of the hydrogel.

FIG. 2 shows the percentage drying of PVP hydrogel (20% PVP, 1% agar) atdifferent concentrations of PEG. The drying patterns show similar curvesfor 0 to 5% PEG. Loss of water is 65% of the initial weight of thehydrogel after 55 hours. PVP having 10% PEG shows a better dryingpattern with only 40% weight loss after the drying period.

Cross-linking agents can be used to improve the gel fraction.Polyethylene glycol dimethacrylate was studied in a PVP hydrogelformulation of 15% PVP and 1% agar at 10% PEG. Table 2 shows theresults. The data obtained indicate that this cross-linking agentimproves the cross-linking of this PVP hydrogel. The gel fractionincreases with increasing amount of cross-linking agent. TABLE 2 Effectof polyethylene glycol dimethacrylate on the gel fraction of PVPhydrogel (15% PVP, 1% agar, 10% PEG) % Cross-linker Gel fraction 0 0.780.5 0.88 1 0.96 2 1.00

FIG. 3 shows the swelling pattern of this hydrogel. The percentageswelling decreases slightly with increasing amount of cross-linkingagent. The amount of polyethylene glycol dimethacrylate does not affectthe drying pattern of the PVP hydrogel. This is apparent from FIG. 4.The curves indicate similar drying patterns. It was observed that thetransparency of the hydrogel decreases as the amount of cross-linkingagent increases.

FIGS. 5 and 6 show a comparison between a hydrogel according to theinvention (15% PVP, 1% agar, 10% PEG, 0.1% cross-linking agent, 0.1%surfactant and 0.1% allantonin) and the commercially available AQUA GELwith regard to drying and swelling patterns.

1. A method of preparing a hydrogel wound covering from polymers by irradiation cross-linking, comprising the steps of providing an initial aqueous solution comprising at least 15% of a synthetic polymer cross-linkable by irradiation, based on the weight of the mixture, at least one humectant, a natural polymer and water, pouring the aqueous solution into a mould for shaping, allowing the initial aqueous solution to mature in the mould during a period of time sufficient to obtain a semi-product having at least a content of 35% of synthetic polymer, removing the semi-product thus shaped from the mould, and subjecting the semi-product to irradition in order to cross-link the semi-product.
 2. A method according to claim 1, wherein the synthetic polymer cross-linkable by irradiation is polyvinylpyrrolidone.
 3. A method according to claim 2, wherein the polyvinylpyrrolidone has a weight average molecular weight of at least 300,000 Dalton.
 4. A method according to one of the preceding claims, wherein the humectant is polyethylene glycol.
 5. A method according to claim 4, wherein the humectant is present in the initial aqueous solution in the range of 0.5-10% by weight.
 6. A method according to claim 4, wherein the content of humectant in the semi-product is at most 20% by weight.
 7. A method according to one of the preceding claims, wherein the natural polymer is agar.
 8. A method according to one of the preceding claims, wherein the natural polymer is present in the range of 0.5-3.0% by weight.
 9. A method according to one of the preceding claims, wherein the initial aqueous solution also comprises a cross-linking agent.
 10. A method according to one of the preceding claims, wherein the maturation period of time is at least 15 hours.
 11. A method according to one of the preceding claims, further comprising the step of applying an adhesive plastic foil for adhesion to the skin onto the semi-product that has been removed from the mould.
 12. A method according to claim 11, further comprising the step of sealing the semi-product and adhesive plastic foil into a suitable packaging material prior to the irradiation treatment.
 13. Hydrogel wound covering, comprising a radiation cross-linked synthetic polymer in an amount of at least 35% by weight, a humectant and a natural polymer.
 14. Hydrogel wound covering according to claim 13, comprising a crosslinked polyvinylpyrrolidone, at most 10% by weight humectant and 0.5-3% by weight natural polymer.
 15. Hydrogel wound dressing according to claim 13 or 14, comprising a crosslinked polyvinylpyrrolidone having an initial weight average molecular weight of at least 300,000 Dalton.
 16. Packaged hydrogel wound dressing article comprising a hydrogel of a radiation crosslinked synthetic polymer in an amount of at least 35% by weight, a humectant and a natural polymer. 